Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors

Yuan-Yuan Hei; Ying Shen; Jin Wang; Hao Zhang; Hong-Yi Zhao; Minhang Xin; Yong-Xiao Cao; Yan Li; San-Qi Zhang

doi:10.1016/j.bmc.2018.03.025

Synthesis and evaluation of 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine as new EGFR inhibitors

Bioorg Med Chem. 2018 May 1;26(8):2173-2185. doi: 10.1016/j.bmc.2018.03.025. Epub 2018 Mar 16.

Authors

Yuan-Yuan Hei¹, Ying Shen¹, Jin Wang², Hao Zhang¹, Hong-Yi Zhao¹, Minhang Xin¹, Yong-Xiao Cao², Yan Li¹, San-Qi Zhang³

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
² Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China.
³ Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.

PMID: 29576272
DOI: 10.1016/j.bmc.2018.03.025

Abstract

In present study, we described the synthesis and biological evaluation of a new class of EGFR inhibitors containing 2,9-disubstituted 8-phenylthio/phenylsulfinyl-9H-purine scaffold. Thirty-one compounds were synthesized. Among them, compound C9 displayed the IC₅₀ of 29.4 nM against HCC827 cell line and 1.9 nM against EGFR^L858R. Compound C12 showed moderate inhibitory activity against EGFR^{L858R/T790M/C797S} (IC₅₀ = 114 nM). Western bolt assay suggested that compound C9 significantly inhibited EGFR phosphorylation. In vivo test, compound C9 remarkably exhibited inhibitory effect on tumor growth at 5.0 mg/kg by oral administration in established nude mouse HCC827 xenograft model. These results indicate that the 2,9-disubstituted 8-phenylsulfinyl/phenylsulfinyl-9H-purine derivatives can act as potent EGFR(L858R) inhibitors and effective anticancer agents. Additionally, optimization of compound C12 may result in discovering the fourth-generation EGFR-TKIs.

Keywords: Anticancer agent; Antiproliferative effects; Drug design; EGFR-TK inhibitor; Purine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Oral
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Female
Humans
Mice
Mice, Nude
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / pathology
Protein Kinase Inhibitors / chemical synthesis*
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Structure, Tertiary
Purines / chemistry*
Purines / pharmacology
Purines / therapeutic use
Structure-Activity Relationship
Transplantation, Heterologous

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Purines
ErbB Receptors